title: Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions.
abstract: OBJECTIVE
  Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both.
  
  
  METHODS
  Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2.
  
  
  RESULTS
  Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively.
  
  
  CONCLUSIONS
  These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy.
authors.affiliation: Authors' Affiliations: Departments of Urology and Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan; and Exelixis Inc., South San Francisco, California.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.forename: Honglai
authors.initials: H
authors.lastname: Zhang
authors.forename: Andreas
authors.initials: A
authors.lastname: Karatsinides
authors.forename: Jill M
authors.initials: JM
authors.lastname: Keller
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kozloff
authors.forename: Dana T
authors.initials: DT
authors.lastname: Aftab
authors.forename: Frauke
authors.initials: F
authors.lastname: Schimmoller
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010006:Osteoblasts / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; C558660:cabozantinib